MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancer

Background: While PARP inhibitors and CDK4/6 inhibitors, the two dasses of FDA-approved agents, have shown promising clinical benefits, there is an urgent need to develop new therapeutic strategies to improve dinical response. Meanwhile, extending the utility of these inhibitors beyond their respective molecularly defined cancer types is challenging and will likely require biomarkers predictive of treatment response especially when used in a combination drug development setting. Methods: The effects of PARP inhibitor Olaparib and CDK4/6 inhibitor Palbociclib on ovarian cancer cells lines including those of high-grade serous histology were examined in vitro and in vivo. We investigated the molecular mechanism underlying the synergistic effects of drug combination. Findings: We show for the first time that combining PARP and CDK4/6 inhibition has synergistic effects against MYC overexpressing ovarian cancer cells both in vitro and in vivo. Mechanistically, we find that Palbociclib induces homologous recombination (HR) deficiency through downregulation of MYC-regulated HR pathway genes, causing synthetic lethality with Olaparib. We further demonstrate that MYC expression determines sensitivity to combinatorial treatment with Olaparib and Palbocidib. Interpretation: Our data provide a rationale for clinical evaluation of therapeutic synergy of these two dasses of inhibitors in ovarian cancer patients whose tumors show high MYC expression and who do not respond to PARP inhibitors or CDK4/6 inhibitors monotherapies. (C) 2019 Published by Elsevier B.V.